Human Epidermal growth factor Receptor 2 (HER2/ErbB2) is a protein giving higher aggressiveness in breast cancers. It is a member of the ErbB protein family, more commonly known as the epidermal growth factor receptor family. ErbB2 is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. It is encoded within the genome by HER2/neu, a known proto-oncogene. The HER2/neu gene is a proto-oncogene located at the long arm of human chromosome 17(17q21-q22).
Approximately 15-20 percent of breast cancers have an amplification of the HER2/neu gene or overexpression of ErbB2. Overexpression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis. Overexpression also occurs in other cancer such as ovarian cancer, stomach cancer, and biologically aggressive forms of uterine
ErbB2 also plays a role in neurological and psychiatric disorders. Impaired myelin formation and maintenance have been implicated in various neurological and psychiatric disorders including schizophrenia, multiple sclerosis, and Charcot-Marie-Tooth neuropathy disease (Mei L, et al. Nat Rev Neurosci. 2008 9:437-452; Shy Me. J Neurol Sci. 2006 242(1-2):55-66). In the peripheral nervous system (PNS), neuregulin 1 (NRG1), which was originally identified as a 44-kD glycoprotein that interacts with the HER2/ErbB2 receptor tyrosine kinase, has emerged as a key axon-derived factor that regulates myelination. Disruption of NRG1 signaling by ablating either the EGF domain that is contained in all isoforms or type III isoform leads to an almost complete loss of Schwann cells (SCs) and of the sensory and motor neurons that they support (Meyer D, et al. Nature. 1995 378:386-390; Wolpowitz D, et al. Neuron. 2000 25:79-91). NRG1 does not actually interact with HER2/ErbB2 (Tzahar E, et al. Mol Cell Biol. 1996 16:5276-87). Instead, ErbB2 forms a heterodimer with ErbB3, which can bind NRG1 to be functional (Guy P M, et al. Proc. Natl Acad Sci USA. 1994 91:8132-86; Adlkofer K, et al. Glia. 2000 29:104-11). Mutation of NRG1, ErbB2, or ErbB3 genes causes severe deficits of peripheral neurons and SCs (Meyer D, et al. Nature. 1995 378:386 90; Wolpowitz D, et al. Neuron. 2000 25:79-91; Garratt A N, et al. J Cell Biol. 2000 148:1035-46; Lee K F, et al. Nature. 1995 378:394-98; Riethmacher D, et al. Nature. 1997 389:725-30; Woldeyesus M T, et al. Genes Dev. 1999 13:2538-48). Moreover, disruption of NRG1/ErbB signaling by a dominant negative approach leads to deficits in myelinating and nonmyelinating SCs (Chen S, et al. Nat Neurosci. 2003 6:1186-93; Chen S, et al. J Neurosci. 2006 26:3079-86).
The monoclonal antibody trastuzumab (Herceptin®) is a humanized monoclonal antibody that binds to the domain IV of the extracellular segment of the HER2/ErbB2 receptor. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab induces some of its effect by downregulation of HER2/ErbB2, leading to disruption of receptor dimerization and signaling through the downstream PI3K cascade. Another monoclonal antibody, Pertuzumab, which inhibits dimerization of HER2 and HER3 receptors, is in advanced clinical trials.
Unfortunately, treatment of breast cancers overexpressing ErbB2 with trastuzumab (Herceptin®) results in some patients developing cardiac dysfunction. The adverse effect is increased significantly in those patients who also receive the chemotherapeutical agent anthracycline. ErbB2-deficient cardiac myocytes are more susceptible to anthracycline-induced cytotoxicity (Negro, A, et al. Recent Progress in Hormone Research 2004 59:1-12). These results suggest that ErbB2 signaling in the heart is essential for the prevention of dilated cardiomyopathy. Thus, there is a need for new therapies for treating ErbB2-related disorders.
It is an object of the invention to provide alternative compositions and methods for modulating HER2/ErbB2 activity to treat HER2/ErbB2-mediated disorders or conditions.
It is another object of the invention to provide methods and compositions to treat HER2/ErbB2-mediated neurological disorders.